It is generally known in the art that the nature of the immune response raised against a particular vaccine antigen is important to the overall effectiveness of the vaccine. In the case of carbohydrate antigens, a large variety of approaches has been explored in attempts to enhance their immunogenicity, including chemical modification (Jennings, et al. in Towards Better Carbohydrate Vaccines Bell and Torrigiani (eds) pp 11-17, J. Wiley and Sons, London, 1987), administration with adjuvants, noncovalent complexing with proteins, covalent attachment to immunogenic protein carriers (Schneerson, et al. in Towards Better Carbohydrate Vaccines, supra pp 307-327), and replacement of the carbohydrate epitope by a protein replica, either peptides synthesized de novo (so-called mimitopes, Geyson, et al. in Towards Better Carbohydrate Vaccines, supra, pp 103-118) or antiidiotypic antibodies (Soederstroem in Towards Better Carbohydrate Vaccines, supra, pp 119-138).
Covalent attachment of carbohydrate antigens to immunogenic T-dependent protein carriers is known (see, e.g, Schneerson, et al., 152:361-376 (1980); Lepow, et al., J. Pediatr. 106:185-189 (1985); Chu, et al., Infect. Immun., 50:245-256 (1983); Marborg et al., Am. Chem. Soc.) 108:5282-5287 (1985); Anderson et al., Infect. Immun., 39:233-238 (1983); Bartoloni, et al., Vaccine 13:463-470 (1995); and Wessels, et al., J. Infect. Dis. 171:879-884 (1995)).
Immunogenic peptides, containing epitopes recognized by T helper cells, have been found to be useful in inducing immune responses. The use of helper peptides to enhance antibody responses against particular determinants is described for instance in Hervas-Stubbs, et al., Vaccine 12:867-871 (1994).
Although allele-specific polymorphic residues that line the peptide binding pockets of MHC alleles tend to endow each allele with the capacity to bind a unique set of peptides, there are many instances in which a given peptide has been shown to bind to more than one MHC allele. This has been best documented in the case of the human DR isotype, in which it has been noted that several DR alleles appear to recognize similar motifs, and independently, several investigators reported degenerate binding and/or recognition of certain epitopes in the context of multiple DR types, leading to the concept that certain peptides might represent xe2x80x9cuniversalxe2x80x9d epitopes (Busch, et al., Int. Immunol. 2:443-451 (1990); Panina-Bordignon, et al., Eur. J. Immunol. 19:2237-2242 (1989); Sinigaglia, et al., Nature 336:778-780 (1988); O""Sullivan, et al., J. Immunol. 147:2663-2669 (1991); Roache, et al., J. Immunol. 144:1849-1856 (1991); Hill, et al., J. Immunol. 147:189-197 (1991)). Although, the previously reported peptides do have the capacity to bind to several DR alleles, they are by no means universal.
Pan-DR binding (PADRE) peptides have been described in WO 95/07707 and Alexander, et al., Immunity 1:751-761 (1994).
For example, preferred pan DR peptides have the formula R1-R2-R3-R4-R5, where R1 is a D-amino acid followed by alanine or lysine, R2 is cyclohexylalanine, tyrosine, or phenylalanine, R3 is 3 or 4 amino acids each of which is selected from the group consisting of alanine, isoleucine, serine and valine; R4 is threonine-leucine-lysine, lysine-threonine, or tryptophan-threonine-leucine-lysine; and R5 consists of 2 to 4 amino acids followed by a D-amino acid, where each 2 to 4 amino acids is independently selected from the group consisting of alanine, serine, and valine.
The sentence above is not new matter because the sentence (from page 4, lines 17-28 of U.S. Ser. No. 08/305,871) is incorporated by reference in the present application. The present application is a continuation-in-part of U.S. Ser. No. 08/305,871, filed Sep. 14, 1994, now U.S. Pat. No. 5,736,142, issued Apr. 7, 1998. U.S. Ser. No. 08/305,871 is incorporated by reference in the present application on page 1, lines 12-14. Therefore, the language was always a part of the specification and is not new matter. These peptides have been shown to help in the generation of a CTL response against desired protein antigens.
However, the prior art fails to teach compounds or compositions that provide an effective humoral response. For example, in the case of carbohydrate immunogens, antibody responses have traditionally been predominantly of short-term expression of IgM followed by an inconsistent IgG response. Such a response is generally not as effective in producing long term protection against the immunogen as an IgG-mediated response. The present invention addresses these and other needs.
The present invention provides compositions comprising a PADRE oligopeptide of less than about 50 amino acid residues and an antigenic determinant, wherein the oligopeptide and antigenic determinant are optionally covalently attached to each other. The antigenic determinant can be from a bacterium, a virus, a cancer cell, a fungus, or a parasite. When the PADRE oligopeptide and the antigenic determinant are covalently attached to each other, they will be either directly linked or attached by means of a linking group which preferably comprises a cysteine residue.
In one group of embodiments, the PADRE peptide is selected from the group consisting of aAXAAAKTAAAAa, aAXAAAATLKAAa, aAXVAAATLKAAa, aAXIAAATLKAAa, aKXVAAWTLKAAa, and aKFVAAWTLKAAa wherein a is D-alanine, A is L-alanine, X is cyclohexylalanine, K is lysine, T is threonine, L is leucine, V is valine, I is isoleucine, W is tryptophan, and F is phenylalanine. More preferably, the PADRE peptide is aKXVAAWTLKAAa. In other groups of embodiments, the termini of the peptides can be either in the D- or L-form.
Additionally, the present invention provides a composition for eliciting an immune response to an immunogenic carbohydrate, the composition comprising a PADRE oligopeptide of less than about 50 residues and at least one carbohydrate epitope. Preferably, the PADRE peptide has the formula R1-R2-R3-R4-R5, (SEQ ID NOS:28-30 No: 2) proceeding from the N-terminus to the C-terminus, wherein R1 consists of at least 2 residues; R2 is selected from the group consisting of a cyclohexylalanine residue, a tyrosine residue, a phenylalanine residue and conservative substitutions therefor; R3 is 3 to 5 amino acid residues; R4 is selected from the group consisting of threonine-leucine-lysine, lysine-threonine, and tryptophan-threonine-leucine-lysine, and conservative (SEQ ID NO:1) substitutions therefor; and R5 consists of at least 2 residues.